Structural basis of simultaneous recruitment of the transcriptional regulators LMO2 and FOG1/ZFPM1 by the transcription factor GATA1

Abstract

The control of red blood cell and megakaryocyte development by the regulatory protein GATA1 is a paradigm for transcriptional regulation of gene expression in cell lineage differentiation and maturation. Most GATA1-regulated events require GATA1 to bind FOG1, and essentially all GATA1-activated genes are cooccupied by a TAL1/E2A/LMO2/LDB1 complex; however, it is not known whether FOG1 and TAL1/E2A/LMO2/LDB1 are simultaneously recruited by GATA1. Our structural data reveal that the FOG1-binding domain of GATA1, the N finger, can also directly contact LMO2 and show that, despite the small size (<50 residues) of the GATA1 N finger, both FOG1 and LMO2 can simultaneously bind this domain. LMO2 in turn can simultaneously contact both GATA1 and the DNA-binding protein TAL1/E2A at bipartite E-box/WGATAR sites. Taken together, our data provide the first structural snapshot of multiprotein complex formation at GATA1-dependent genes and support a model in which FOG1 and TAL1/E2A/LMO2/LDB1 can cooccupy E-box/WGATAR sites to facilitate GATA1-mediated activation of gene activation.